U.S. patent application number 10/492674 was filed with the patent office on 2006-07-27 for powdery active ingredient formulations.
Invention is credited to Peter Baur, Heike Bunjes, Jurgen Hinderer, Albert Hinnen, Jonas Hinnen, Bernd Klinksiek, Astrid Mauler-Machnik, Karl Reizlein, Anne Suty-Heinze, Kirsten Westesen.
Application Number | 20060165742 10/492674 |
Document ID | / |
Family ID | 7702888 |
Filed Date | 2006-07-27 |
United States Patent
Application |
20060165742 |
Kind Code |
A1 |
Reizlein; Karl ; et
al. |
July 27, 2006 |
Powdery active ingredient formulations
Abstract
Novel pulverulent active substance formulations composed of at
least one active substance which is solid at room temperature, at
least one dispersant, polyvinyl alcohol and if desired, additives,
the individual active substance particles being enveloped by a coat
of polyvinyl alcohol, being present in the amorphous state, and
having diameter in the nanometer range, a process for producing the
novel formulations and their use for the application of the active
substance they comprise and also a device for carrying out the
production process.
Inventors: |
Reizlein; Karl; (Koln,
DE) ; Klinksiek; Bernd; (Bergisch Gladbach, DE)
; Hinderer; Jurgen; (Oakdale, PA) ; Baur;
Peter; (Eppstein, DE) ; Suty-Heinze; Anne;
(Langenfeld, DE) ; Mauler-Machnik; Astrid;
(Leichlingen, DE) ; Bunjes; Heike; (Jena, DE)
; Westesen; Kirsten; (Niederrossla, DE) ; Hinnen;
Jonas; (Marburg, DE) ; Hinnen; Albert;
(Marburg, DE) |
Correspondence
Address: |
BAYER CROPSCIENCE LP;Patent Department
100 BAYER ROAD
PITTSBURGH
PA
15205-9741
US
|
Family ID: |
7702888 |
Appl. No.: |
10/492674 |
Filed: |
October 17, 2002 |
PCT Filed: |
October 17, 2002 |
PCT NO: |
PCT/EP02/11613 |
371 Date: |
November 28, 2005 |
Current U.S.
Class: |
424/405 ;
424/489 |
Current CPC
Class: |
A01N 25/28 20130101;
A01N 25/14 20130101; A61K 9/5026 20130101; A61K 9/5138
20130101 |
Class at
Publication: |
424/405 ;
424/489 |
International
Class: |
A01N 25/00 20060101
A01N025/00; A61K 9/14 20060101 A61K009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 18, 2001 |
DE |
101 51 392.5 |
Claims
1-5. (canceled)
6. A pulverulent active substance formulation comprising: at least
one active substance which is solid at room temperature; at least
one dispersant; polyvinyl alcohol; and optionally one or more
additives; the active substance being present in the form of
individual particles, said active substance particles being coated
with a coat of polyvinyl alcohol, said polyvinyl alcohol coated
active substance particles additionally being present in an
amorphous state and having a diameter in the nanometer region.
7. A process for producing the pulverulent active substance
formulation according to claim 6, comprising: a) suspending at
least one active substance which is solid at room temperature, at
least one dispersant, and optionally additives in water, at room
temperature; b) heating the resultant suspension until the solid
components it comprises melt to obtain a dispersion comprising said
melted solid components in said suspension; c) homogenizing said
first dispersion and then rapidly cooling it to a temperature below
the solidification point of said dispersed components to form
pulverulent particles of said active substance in said suspension;
and d) thereafter adding an aqueous solution of polyvinyl alcohol,
alone or in a mixture with other coating materials and optional
additives to the suspension comprising the pulverulent particles of
active substance to coat at least a plurality of said particles
with a polyvinyl alcohol coating, and immediately thereafter
subjecting the resultant suspension of polyvinyl alcohol coated
pulverulent particles of active substance to spray drying to obtain
the pulverulent active substance formulation according to claim
6.
8. A method of applying an active substance to a target organism
and/or its habitat comprising delivering an effective amount of an
active substance in a pulverulent active substance formulation
according to claim 6, said formulation optionally including one or
more extenders and/or surface-active substances, to the target
organism and/or its habitat.
9. An apparatus for producing a pulverulent active substance
formulation according to claim 6, comprising: a vessel, said vessel
including a stirrer for stirring the contents of said vessel, said
vessel having an outlet for the discharge of the contents of said
vessel from said vessel; a first pump in fluid communication with
said discharge outlet of said vessel; a heat exchanger in fluid
communication with said first pump; a jet disperser in fluid
communication with said heat exchanger; a condenser having an inlet
and outlet, the inlet of said condenser in fluid communication with
said heat exchanger; a cooling circuit provided about said
condenser, said cooling circuit including a second pump and
providing a fluid communication loop, said loop in fluid
communication from said outlet of said condenser to said inlet of
said condenser, said loop providing for the optional recirculation
of a fluid from the outlet of said condenser back to the inlet of
said condenser through said second pump to cool said fluid; a
metering pump in fluid communication with the outlet of said
condenser; optionally, a mixing vessel in fluid communication with
said metering pump; and a spray dryer in fluid communication with
said metering pump or alternatively, in fluid communication with
said mixing vessel when said mixing vessel is present.
10. The pulverulent active substance produced by the process of
claim 7.
11. A process for producing a pulverulent active substance compris
ing the step of producing said pulverulent active substance with
the apparatus of claim 9.
12. The pulverulent active substance produced by the process of
claim 11.
13. The process of claim 7, further comprising the step of
producing said pulverulent active substance with the apparatus of
claim 9.
14. The pulverulent active substance produced by the process of
claim 13.
15. The method of applying an active substance to a target organism
and/or its habitat of claim 8, wherein the pulverulent active
substance is produced by the process of claim 7.
16. The method of applying an active substance to a target organism
and/or its habitat of claim 8, wherein the pulverulent active
substance is produced with the apparatus of claim 9.
17. The method of applying an active substance to a target organism
and/or its habitat of claim 8, wherein the pulverulent active
substance is produced by the process of claim 7 using the apparatus
of claim 9.
Description
[0001] The present invention relates to new pulverulent active
substance formulations, to a process for preparing them and to
their use for applying the biologically active substances they
include.
[0002] Numerous active substance formulations have already been
disclosed in which the active components are present in a very
finely divided state.
[0003] For instance, WO 94-20 072 and U.S. Pat. No. 5,785,976
describe suspensions of solid active substances that are of low
solubility in water. These formulations can be prepared by melting
solid active substance, heating the dispersion medium to
approximately the temperature of the active substance melt, adding
a water-soluble stabilizer to the dispersion medium and optionally
a lipid-soluble stabilizer to the active substance melt, then
mixing and homogenizing melt and dispersion and cooling the
resultant dispersion. The effectiveness of these formulations in
the freshly prepared state is good. A disadvantage, however, is
that the bioavailability of the active components leaves something
to be desired.
[0004] WO 95-05 164, moreover, discloses formulations of sparingly
water-soluble substances in the form of supercooled melts in which
the substances are liquid, are at least partly in amorphous state
and have diameters in the nanometer range. These formulations are,
however, of limited stability owing to the partially crystalline
state, since recrystallization may occur.
[0005] Furthermore, WO 98-16 105 discloses solid plant treatment
compositions in which the active substances are very finely
divided, are essentially in amorphous form and are surrounded by a
polymeric coat. These formulations are obtained by mixing a liquid
formulation of the active substance with a liquid formulation of
the coating material and removing the solvent from the resultant
mixture. The stability and efficacy of the formulations obtained in
this case, however; are not always sufficient. Moreover, the
procedure is very laborious, since not only solvent but
considerable amounts of water too have to be removed.
[0006] Novel pulverulent active substance formulations have now
been found which are composed of [0007] at least one active
substance which is solid at room temperature, [0008] at least one
dispersant, [0009] polyvinyl alcohol, and [0010] optionally
additives, the individual active substance particles being coated
with a coat of polyvinyl alcohol, being present in an amorphous
state and having a diameter in the nanometer region.
[0011] It has further been found that the pulverulent active
substance formulations of the invention can be produced by [0012]
a) suspending at least one active substance which is solid at room
temperature, at least one dispersant, and optionally additives in
water, at room temperature, [0013] b) heating the resultant
suspension until the solid components it comprises melt, [0014] c)
first homogenizing the dispersion obtained and then rapidly cooling
it to a temperature below the solidification point of the dispersed
components, [0015] d) thereafter adding an aqueous solution of
polyvinyl alcohol, alone or in a mixture with other coating
materials and also, optionally, additives and immediately
thereafter subjecting the resultant dispersion to spray drying.
[0016] Finally it has been found that the pulverulent active
substance formulations of the invention are especially suitable for
the application of the active substances they compnse.
[0017] It is considered extremely surprising that the pulverulent
active substance formulations of the invention are substantially
more stable than the existing preparations constitutionally closest
to them, which are obtainable by melt dispersing, but in which the
individual particles are not encapsulated. Another reason for the
unexpectedness of the stability of the formulations of the
invention is that it is assumed that when the powders are stirred
together with water the polyvinyl alcohol coat dissolves, and it
was therefore feared that the amorphous active substance, which
would then be unprotected, would recrystallize. Contrary to
expectations, however, this effect does not occur.
[0018] The pulverulent active substance formulations of the
invention are also notable for a number of advantages. For
instance, the active substance content is very high as compared
with corresponding existing formulations. This means that just a
small amount of formulation is sufficient to apply the desired
quantity of active component. Another advantage is that the
pulverulent active substance formulations of the invention can be
redispersed readily prior to use and that the bioavailability of
the active components remains at the high level achieved following
production. It is favourable, finally, that the thermal load on the
active substances during the production of the formulations is
comparatively low. Moreover, the preparation of the powder
formulations of the invention requires neither additional carrier
materials nor organic solvents. Furthermore, the process of the
invention can also be used without problems to process active
substances whose melting point is well above 100.degree. C.
[0019] Suitable active substances present in the pulverulent
formulations of the invention are at room temperature solid active
pharmaceutical substances, active agrochemical substances and
aromas.
[0020] Examples that may be mentioned of active pharmaceutical
substances are ibuprofen, clotrimazole, fluconazole, indoxacarb and
ciprofloxazin.
[0021] By agrochemical substances in the present context are meant
all substances customary for plant treatment whose melting point is
above 20.degree. C. With preference mention may be made of
fungicides, bactericides, insecticides, acaricides, nematicides,
molluscicides, herbicides and plant growth regulators.
[0022] Examples of Fungicides Which May be Mentioned are:
[0023] 2-anilino-4-methyl-6-cyclopropylpyrimidine;
2',6'-dibromo-2-methyl-4'-trifluoromethoxy-4'-trifluoromethyl-1,3-thiazol-
e-5-carboxanilide;
2,6-dichloro-N-(4-trifluoromethylbenzyl)benzamide;
(E)-2-methoximino-N-methyl-2-(2-phenoxyphenyl)acetamide;
8-hydroxyquinoline sulfate; methyl
(E)-2-{2-[6-(2-cyanophenoxy)pyrimidine-4-yloxy]phenyl}-3-methoxyacrylate;
methyl (E)-methoximino[alpha-(o-tolyloxy)-o-tolyl]acetate;
2-phenylphenol (OPP), ampropylfos, anilazin, azaconazole,
benalaxyl, benodanil, benomyl, binapacryl, biphenyl, bitertanol,
blasticidin-S, bromuconazole, bupirimate, buthiobate, captafol,
captan, carbendazim, carboxin, chinomethionat (quinomethionate),
chloroneb, chloropicrin, chlorothalonil, chlozolinate, cufraneb,
cymoxanil, cyproconazole, cyprofuram, carpropamid, dichlorophen,
diclobutrazole, dichlofluanid, diclomezin, dicloran, diethofencarb,
difenoconazole, dimethirimol, dimethomorph, diniconazole,
diphenylamine, dipyrithion, ditalimfos, dithianon, dodine,
drazoxolon, epoxyconazole, ethirimol, etridiazole, fenarimol,
fenbuconazole, fenfuram, fenitropan, fenpiclonil, fentin acetate,
fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil,
fluoromide, fluquinconazole, flusilazole, flusulfamide, flutolanil,
flutriafol, folpet, fosetyl-aluminium, fthalide, fuberidazole,
furalaxyl, furmecyclox, fenhexamid, guazatine, hexachlorobenzene,
hexaconazole, hymexazol, imazalil, imibenconazole, iminoctadin,
iprodione, isoprothiolane, iprovalicarb, kasugamycin, mancopper,
mancozeb, maneb, mepanipyrim, mepronil, metalaxyl, metconazole,
methasulfocarb, methfuroxam, metiram, metsulfovax, myclobutanil,
nickel dimethyldithiocarbamate, nitrothal-isopropyl, nuarimol,
ofurace, oxadixyl, oxamocarb, oxycarboxin, penconazole, pencycuron,
phosdiphen, pimaricin, polyoxin, probenazole, prochloraz,
procymidone, propamocarb, propineb, pyrazophos, pyrimethanil,
pyroquilon, quintozene (PCNB), quinoxyfen, tebuconazole,
tecloftalam, tecnazen, thiabendazole, thicyofen,
thiophanate-methyl, thiram, tolclophos-methyl, tolylfluanid,
triadimefon, triadimenol, triazoxide, trichlamid, tricyclazole,
triflumizole, triforine, triticonazole, trifloxystrobin validamycin
A, vinclozolin, zineb, ziram,
2-[2-(1-chloro-cyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-2,4-dihyd-
ro-[1,2,4]-triazole-3-thione
[0024]
3-(1-[2-(4-[2-chlorophenoxy)-5-fluoropyrimid-o-yloxy)-phenyl]-1-(m-
ethoximino)-methyl)-5,6-dihydro-1,4,2,-dioxazine and
[0025]
2-(2-[6-(3-chloro-2-methylphenoxy)-5-fluoropyrimid-4-yloxy]-phenyl-
)-2-methoximino-N-methyl-acetamide.
[0026] Examples of Bactericides Which May be Mentioned are:
[0027] bronopol, dichlorophen, nitrapyrin, octhilinone,
furancarboxylic acid, oxytetracyclin, probenazole, tecloftalam.
[0028] Examples of Insecticides, Acaricides and Nematicides Which
May be Mentioned are:
[0029] abamectin, acephate, acrinathrin, alanycarb, aldicarb,
alphamethrin, amitraz, avermectin, AZ 60541, azadirachtin, azinphos
A, azinphos M, azocyclotin,
4-bromo-2-(4-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)-1H-pyrrol-
e-3-carbonitrile, bendiocarb, bensultap, betacyfluthrin,
bifenthrin, BPMC, brofenprox, bromophos A, bufencarb, buprofezin,
butocarboxin, butylpyridaben, carbaryl, carbofuran,
carbophenothion, cartap, chloethocarb, chloretoxyfos,
chlorfluazuron,
N-[(6-chloro-3-pyridinyl)-methyl]-N'-cyano-N-methyl-ethanimidamide,
chlorpyrifos, chlorpyrifos M, cis-resmethrin, clocythrin,
clofentezine, cyfluthrin, cyhexatin, cypermethrin, cyromazine,
deltamethrin, demeton-M, demeton-S, diafenthiuron, dichlofenthion,
dicliphos, dicrotophos, diethiop, diflubenzuron, dimethoate,
dimethylvinphos, dioxathion, emamectin, esfenvalerate,
ethiofencarb, ethofenprox, fenamiphos, fenazaquin, fenbutatin
oxide, fenobucarb, fenothiocarb, fenoxycarb, fenpropathrin,
fenpyrad, fenpyroximate, fenvalerate, fipronil, fluazuron,
flucycloxuron, flufenoxuron, flufenprox, fonophos, formothion,
fubfenprox, hexaflumuron, hexythiazox, imidacloprid, iprobenfos,
isazophos, isoprocarb, ivermectin, lambda-cyhalothrin, lufenuron,
mevinphos, mesulfenphos, metaldehyde, methacrifos, methamidophos,
methidathion, methiocarb, methomyl, metolcarb, milbemectin,
monocrotophos, moxidectin, naled, NC 184, nitenpyram, oxamyl,
oxydeprofos, permethrin, phosalone, phosmet, pirimicarb, promecarb,
propoxur, prothoate, pymetrozine, pyridaphenthion, pyresmethrin,
pyridaben, pyrimidifen, pyriproxifen, quinalphos, salithion,
sebufos, tebufenozide, tebufenpyrad, tebupirimiphos, teflubenzuron,
tefluthrin, temephos, terbam, tetrachlorvinphos, thiacloprid,
thiafenox, thiamethoxam, thiodicarb, thiofanox, thiomethon,
thuringiensin, tralomethrin, transfluthrin, triarathene, triazuron,
trichlorfon, triflumuron, trimethacarb, vamidothion, XMC,
xylylcarb, zetamethrin.
[0030] Examples of Molluscicides Which May be Mentioned are
Metaldehyde and Methiocarb.
[0031] Examples of Herbicides Which May be Mentioned are:
[0032] Anilides, such as, for example, diflufenican and propanil;
arylcarboxylic acids, such as, for example, dichloropicolinic acid,
dicamba and picloram; aryloxyalkanoic acids, such as, for example,
2,4-D, 2,4-DB, 2,4-DP, fluroxypyr, MCPA, MCPP and triclopyr;
aryloxy-phenoxy-alkanoates, such as, for example, diclofop-methyl,
fenoxaprop-ethyl, haloxyfop-methyl and quizalofop-ethyl; azinones,
such as, for example, chloridazon and norflurazon; carbamates, such
as, for example, chlorpropham, desmedipham, phenmedipham and
propham; chloroacetanilides, such as, for example, alachlor,
metazachlor and propachlor; dinitroanilines, such as, for example,
oryzalin, pendimethalin and trifluralin; diphenyl ethers, such as,
for example, acifluorfen, bifenox, fluoroglycofen, fomesafen,
halosafen, lactofen and oxyfluorfen; ureas, such as, for example,
chlortoluron, diuron, fluometuron, isoproturon, linuron and
methabenzthiazuron; hydroxylamines, such as, for example,
alloxydim, cycloxydim, sethoxydim and tralkoxydim; imidazolinones,
such as, for example, imazethapyr, imazamethabenz, imazapyr and
imazaquin; nitriles, such as, for example, bromoxynil, dichlobenil
and ioxynil; oxyacetamides, such as, for example, mefenacet;
sulfonylureas, such as, for example, amidosulfuron,
bensulfuron-methyl, chlorimuron-ethyl, chlorsulfuron, cinosulfuron,
metsulfuron-methyl, nicosulfuron, primisulfuron,
pyrazosulfuron-ethyl, thifensulfuron-methyl, triasulfuron and
tribenuron-methyl; thiolcarbamates, such as, for example, diallate
and triallate; triazines, such as, for example, atrazine,
cyanazine, simazine, simetryn, terbutryne and terbutylazine;
triazinones such as, for example, hexazinon, metamitron and
metribuzin; others, such as, for example, aminotriazole,
benfuresate, bentazone, clomazone, clopyralid, difenzoquat,
dithiopyr, ethoftimesate, fluorochloridone, glufosinate,
glyphosate, isoxaben, pyridate, quinchlorac, quinmerac, sulfosate
and tridiphane.
4-Amino-N-(1,1-dimethylethyl)-4,5-dihydro-3-(1-methylethyl)-5-oxo-1H-1,2,-
4-triazole-1-carboxamide and
2-((((4,5-dihydro-4-methyl-5-oxo-3-propoxy-1H-1,2,4-triazol-1-yl)carbonyl-
)amino)sulfonyl)-methyl benzoate may also be mentioned.
[0033] Examples of Plant Growth Regulators Which May be Mentioned
are Chlorocholine Chloride and Ethephon.
[0034] Dispersants suitable in the case of the formulations of the
invention include all customary nonionogenic, anionic, cationic and
zwitterionic substances, having the desired surface-active
properties, that are normally used in such formulations. These
substances include reaction products of fatty acids, fatty acid
esters, fatty alcohols, fatty amines, alkylphenols or
alkylarylphenols with ethylene oxide and/or propylene oxide, and
also their sulphuric esters, phosphoric monoesters and phosphoric
diesters, and also reaction products of ethylene oxide with
propylene oxide, and also alkylsulphonates, alkyl sulphates, aryl
sulphates, tetraalkylammonium halides, trialkylarylammonium halides
and alkylamine sulphonates. The dispersants can be used
individually or else in a mixture. With preference mention may be
made of reaction products of caster oil with ethylene oxide in a
molar ratio of from 1:20 to 1:60, reaction products of
C.sub.6-C.sub.20 alcohols with ethylene oxide in a molar ratio of
from 1:5 to 1:50, reaction products of fatty amines with ethylene
oxide in a molar ratio of from 1:2 to 1:20, reaction products of 1
mol of phenol with 2 to 3 mol of styrene and from 10 to 50 mol of
ethylene oxide, reaction products of C8-C.sub.12 alkylphenols with
ethylene oxide in a molar ratio of from 1:5 to 1:30,
alkylpolyglycosides, C.sub.8-C.sub.16 alkylbenzenesulphonic salts,
such as calcium salts, monoethanolammonium salts, diethanolammonium
salts and triethanolammonium salts, for example.
[0035] As examples of nonionic dispersants mention may be made of
the products known under the names Pluronic PE 10 100 and Pluronic
F 68 (from BASF) and Atlox 4913 (from Uniqema). Also suitable are
tristyrylphenyl ethoxylates. As examples of anionic dispersants
mention may be made of the product from Bayer AG known under the
name Baykanol SL (a condensation product of sulphonated ditolyl
ether with formaldehyde), which is available commercially, and
phosphated or sulphated tristyrylphenol ethoxylates, in which case
specific mention may be made of Soprophor FLK, Soprophor 3D 33 and
Soprophor 4D 384 (from Rhodia).
[0036] As dispersants mention may also be made by way of example of
copolymers of ethylene oxide and propylene oxide, reaction products
of tristyrylphenol with ethylene oxide and/or propylene oxide, such
as tristyrylphenol ethoxylate containing on average 24 ethylene
oxide groups, tristyrylphenol ethoxylate with on average 54
ethylene oxide groups or. tristyrylphenol ethoxylate propoxylate
with on average 6 ethylene oxide groups and 8 propylene oxide
groups, and also phosphated or sulphated tristyrylphenol
ethoxylates, such as phosphated tristyrlphenol ethoxylate with an
average of 16 ethylene oxide groups, sulphated tristyrylphenol
ethoxylate with an average of 16 ethylene oxide groups or ammonium
salt of phosphated tristyrylphenol ethoxylate with on average 16
ethylene oxide groups, and also phospholipids, such as lecithin,
optionally as a mixture with gall salts, such as sodium
glucocholate, and also liguinsulphonates. Furthermore, substances
having wetting agent properties are also suitable. With preference
mention may be made of alkylphenol ethoxylates,
dialkylsulphosuccinates, such as sodium diisooctylsulphosuccinate,
lauryl ether sulphates, and polyoxyethylene-sorbitan fatty acid
esters.
[0037] Polyvinyl alcohol in the present case refers both to
water-soluble polymerization products of vinyl alcohol and to
water-soluble, partially hydrolysed polymers of vinyl acetate.
Preference is given to polyvinyl alcohol having an average
molecular weight of from 10,000 to 200,000.
[0038] As an example mention may be made of the product from
Clariant known under the tradename Mowiol.RTM. 3-83. Preference is
also given to partially hydrolysed polyvinyl acetate having an
average molecular weight of from 13,000 to 130,000 with an acetate
group content of between 1 and 28%. In the case of Mowiol.RTM. 3-83
the stated numbers have the following meanings: 3 describes the
viscosity of a 4% strength aqueous solution at 20.degree. C. in
mPas, 83 indicates the degree of hydrolysis in mol %.
[0039] Particularly suitable for use in the present case are
polyvinyl alcohols obtained by partial hydrolysis of polyvinyl
acetate, having a degree of hydrolysis of from 72 to 99 mol % and a
viscosity of from 2 to 40 mPas, with particular preference between
3 and 18 mPas, measured on a 4% strength aqueous solution at
20.degree. C. Both individual examples of these partially
hydrolysed polyvinyl acetates and also mixtures are suitable.
[0040] Suitable additives which may be present in the formulations
of the invention include penetrants, defoamers, low-temperature
stabilisers, preservatives, dyes, redispersants, disintegrants,
inert fillers, and film formers.
[0041] Suitable penetrants in the present context are all
substances which are commonly used to enhance the penetration of
active agrochemical substances into plants. Preference is given to
alkanol alkoxylates of the formula R--O-(-AO).sub.mH (I) in which
[0042] R is straight-chain or branched alkyl having 4 to 20 carbon
atoms, [0043] AO is an ethylene oxide radical, a propylene oxide
radical, a butylene oxide radical or mixtures of ethylene oxide and
propylene oxide radicals, and [0044] m is numbers from 2 to 30.
[0045] One particularly preferred group of penetrants are alkanol
alkoxylates of the formula R--O-(-EO--).sub.n--H (Ia) in which
[0046] R is as defined above, [0047] EO is
--CH.sub.2--CH.sub.2--O-- and [0048] n is numbers from 2 to 20.
[0049] Another particularly preferred group of penetrants are
alkanol alkoxylates of the formula
R--O(-EO--).sub.p--(--PO--).sub.q--H (Ib) in which [0050] R is as
defined above, [0051] EO is --CH.sub.2--CH.sub.2--O--, [0052] PO is
##STR1## [0053] p is numbers from 1 to 10 and [0054] q is numbers
from 1 to 10.
[0055] Another particularly preferred group of penetrants are
alkanol alkoxylates of the formula
R--O(--PO--).sub.r-(-EO--).sub.s--H (Ic) in which [0056] R is as
defined above, [0057] EO is --CH.sub.2--CH.sub.2--O--, ##STR2##
[0058] r is numbers from 1 to 10 and [0059] s is numbers from 1 to
10.
[0060] Another particularly preferred group of penetrants are
alkanol alkoxylates of the formula
CH.sub.3--(CH.sub.2).sub.t--CH.sub.2--O--(--CH.sub.2--CH.sub.2--O--).sub.-
u--H (Id) in which [0061] t is numbers from 8 to 13 [0062] and
[0063] u is numbers from 6 to 17.
[0064] In the formulae indicated above [0065] R is preferably
butyl, i-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, i-hexyl,
n-octyl, i-octyl, 2-ethylhexyl, nonyl, i-nonyl, decyl, n-dodecyl,
i-dodecyl, lauryl, myristyl, i-tridecyl, trimethylnonyl, palmityl,
stearyl, or eicosyl.
[0066] An example of an alkanol alkoxylate of the formula (Ic) is
2-ethylhexyl alkoxylate of the formula ##STR3## in which [0067] EO
is --CH.sub.2--CH.sub.2--O--, [0068] PO is ##STR4## and the numbers
8 and 6 represent average values.
[0069] Particularly preferred alkanol alkoxylates of the formula
(Id) are compounds of this formula in which [0070] t is numbers
from 9 to 12 and [0071] u is numbers from 7 to 9.
[0072] A general definition of the alkanol alkoxylates is given by
the formulae above. These substances comprise mixtures of
substances of the stated type with different chain lengths. The
indices therefore come out at average values, which can in some
cases deviate from whole numbers.
[0073] By way of example, mention may be made of alkanol alkoxylate
of the formula (Id) in which [0074] t is the average value 10.5 and
[0075] u is the average value 8.4.
[0076] The alkanol alkoxylates of the formulae stated are known or
can be prepared by known methods (cf. WO 98-35 553, WO 00-35 278
and EP-A 0 681 865).
[0077] Suitable defoamers include all substances which can normally
be used for this purpose in agrochemical compositions. Preference
is given to silicone oils and magnesium stearate.
[0078] Suitable low-temperature stabilisers are all substances
which would normally be employed for this purpose in agrochemical
compositions. Examples which may be mentioned include urea,
glycerol and propylene glycol.
[0079] Suitable preservatives include all substances which can
normally be used for this purpose in agrochemical compositions of
this type. Examples that may be mentioned include Preventol.RTM.
(from Bayer AG) and Proxel.RTM..
[0080] Suitable colorants include all substances which can normally
be used for this purpose in agrochemical compositions. Examples
that may be mentioned include titanium dioxide, pigment-grade
carbon black, zinc oxide and blue pigments and also permanent red
FGR.
[0081] Suitable redispersants include all substances which can
normally be used for this purpose in solid agrochemical
compositions. Preference is given to surfactants, swelling agents
and sugars. By way of example mention may be made of lactose, urea,
polyethylene glycol and tetramethylolpropane.
[0082] Suitable disintegrants, as they are known, include
substances suitable for accelerating the breakdown of the powder
formulations of the invention when combined with water. Preference
is given to salts such as sodium chloride and potassium
chloride.
[0083] Suitable inert fillers include all substances which can
normally be used for this purpose in agrochemical compositions.
Preference is given to inorganic particles, such as carbonates,
silicates and oxides, and also to organic substances, such as
urea-formaldehyde condensates. Mention may be made by way of
example of kaolin, rutile, silica, highly disperse silica, silica
gels, and natural and synthetic silicates, and also talc.
[0084] Suitable film formers include water-soluble substances
normally used for this purpose in active substance formulations.
Preference is given to gelatin, water-soluble starch and
water-soluble copolymers of polyvinyl alcohol and
polyvinylpyrrolidone.
[0085] In the pulverulent active substance formulations of the
invention the amount of the individual components can be varied
within a relatively wide range. For instance, the concentrations
[0086] of solid active substances are generally between 10 and 50%
by weight, preferably between 15 and 40% by weight, [0087] of
dispersants are generally between 5 and 50% by weight, preferably
between 7.5 and 40% by weight, [0088] of polyvinyl alcohol are
generally between 10 and 30% by weight, preferably between 15 and
30% by weight, and [0089] of additives are generally between 0 and
50% by weight, preferably between 0 and 40% by weight.
[0090] The pulverulent active substance formulations of the
invention comprise active substance particles each of which is
surrounded by a coat of polyvinyl alcohol, and which are composed
of individual particles each surrounded by a matrix of polyvinyl
alcohol. The coat-forming polyvinyl alcohol may also comprise other
water-soluble, film-forming substances in addition. The particles
are in the amorphous state and have an average diameter in the
nanometer range. Thus, the average particle diameter of the active
substance particles in the polyvinyl alcohol coats (i.e. capsules)
is generally between 20 and 1 000 nm, preferably between 50 and 400
nm.
[0091] In carrying out the process the procedure of the invention
in step (a) is to suspend finely divided, optionally preground
active substance and also dispersant and, if desired, additives in
water with stirring. This step is generally operated at
temperatures of between 10.degree. C. and 30.degree. C., preferably
at room temperature.
[0092] In the next step (b) of the process of the invention the
resulting suspension is heated so that the solid components
employed melt and an emulsion is formed in which the melt is
distributed in the form of droplets in the aqueous phase. This step
is operated at temperatures above the melting point of the
respective active substance, generally thus at temperatures between
40.degree. C. and 220.degree. C., preferably between 50.degree. C.
and 220.degree. C. Heating preferably takes place at a rate such
that the emulsion state is present only for a short time.
[0093] The resultant emulsion (i.e. dispersion of melt in droplet
form in the water phase) is first of all homogenised in step (c) of
the process of the invention, using a jet disperser, so as to give
a very fine dispersion. This dispersion is thereafter cooled
rapidly to a temperature below the solidification point of the
dispersed melt.
[0094] Homogenization in a jet disperser, also referred to as melt
dispersing, takes place in general at temperatures between
40.degree. C. and 220.degree. C., but in any case above the melting
point of the solid components employed. Subsequent cooling is to a
temperature below the melting point of the solid components, so
that a very fine dispersion of solidified droplets in the aqueous
phase is formed. In certain case, however, it is also possible to
produce emulsions by cooling to temperatures above the
solidification point of the melt.
[0095] In the course of melt dispersing it is general procedure to
operate at elevated pressure, preferably between 50 bar and 1 600
bar, more preferably between 60 bar and 1 000 bar.
[0096] In step (d) of the process of the invention the procedure
adopted is to add an aqueous solution of polyvinyl alcohol, alone
or in a mixture with other coating materials and also, optionally,
with additives to the very fine dispersion prepared, in which the
droplets present beforehand have generally solidified, for the
purpose of encapsulation, and immediately thereafter to subject the
resultant mixture to spray drying.
[0097] For the addition of the aqueous solution in step (d) it is
general procedure to operate at temperatures between 10.degree. C.
and 50.degree. C., preferably between 20.degree. C. and 40.degree.
C. For the spray drying step the temperatures can be varied within
a relatively wide range. Operation is generally carried out at air
entry temperatures of between 100.degree. C. and 200.degree. C.,
preferably between 120.degree. C. and 180.degree. C., and air exit
temperatures of between 50.degree. C. and 100.degree. C.,
preferably between 60.degree. C. and 90.degree. C.
[0098] It is also possible to introduce the emulsion into the spray
dryer directly without cooling, i.e. above the melting temperature
of the active substance present. In that case cooling only takes
place in the spray dryer, in the case for example of cooling to
80.degree. C. Accordingly, the droplets of active substance only
solidify after or during the encapsulation to form solid particles
in the spray-dried powder.
[0099] In one particular variant of the process of the invention it
is, however, also possible to use freeze drying to remove the water
present. This method is appropriately employed when the active
substances are unstable at relatively high temperatures.
[0100] Both spray drying and freeze drying are operated so that
only a very low level of residual moisture remains in the powder
formulation. Drying is generally taken to a point where the
residual moisture content lies below 1% by weight.
[0101] If aqueous polyvinyl alcohol solution is added as additive
as early as in step a) when the process of the invention is being
carried out, there is no need to add this capsule-forming coating
material in step d).
[0102] When conducting the process of the invention, the amounts of
the individual constituents are chosen so that in the resultant
powder formulation the components are present in the proportions
already indicated above.
[0103] The Process of the Invention can be Carried Out Either
Continuously or Batchwise.
[0104] For carrying out the process of the invention it is
preferred to use a new apparatus, composed of [0105] a vessel
provided with a stirrer and connected via [0106] a heat exchanger,
[0107] to which there is connected ajet disperser, from which a
pipeline leads [0108] to a cooling circuit provided with a pump,
the output line of which is connected to [0109] a metering pump and
also, where appropriate, to a mixing vessel, with the pipeline
which leads on from the latter [0110] being connected to a spray
dryer.
[0111] A Diagram of the Apparatus of the Invention is Shown in FIG.
1. In this FIG.
[0112] 1=vessel provided with stirrer
[0113] 2=pump suitable for generating pressure
[0114] 3=heat exchanger
[0115] 4=jet disperser
[0116] 5=condenser in cooling circuit
[0117] 6=pump installed in the cooling circuit
[0118] 7=metering pump for supplying solution
[0119] 8=spray dryer
[0120] The individual components of the apparatus of the invention
are known. Their arrangement in the manner indicated, however, is
new.
[0121] The heat exchanger 3 is an apparatus which allows rapid
heating of the incoming suspension to the desired temperature.
[0122] The jet disperser 4 is constructed so that the incoming
emulsion is dispersed through a nozzle. The fineness of the
dispersion produced is dependent on the homogenising pressure and
on the nozzle used. The smaller the nozzle bore, the finer the
dispersion obtained. Generally speaking, nozzles are used whose
bores are between 0.1 and 1 mm, preferably between 0.2 and 0.7
mm.
[0123] The cooling circuit 5 provided with pump 6 is an apparatus
suitable for minimizing the cooling time of the incoming emulsion.
The emulsion flowing through the condenser 5 is recirculated by
means of the pump 6 with approximately ten times the pumped
circulation flow rate. This cooling circuit ensures cooling of the
admitted emulsion by quenching in the milliseconds range.
[0124] The pump 7 is a metering device which is attached to the
pipeline; leading away from the cooling circuit. At this point in
the apparatus it is also possible to install an additional mixing
vessel with stirrer.
[0125] The spray dryer 8 is a device of this type which is such
that the incoming aqueous solution can have its water removed. The
spray dryer may also be replaced by a freeze dryer.
[0126] Carrying out the process of the invention using the
apparatus of the invention involves in detail, in the first step,
suspending one or more solid active substances, where appropriate
as a mixture with one or more liquid active substances and also,
where appropriate, additives, in a finely divided state in the
vessel 1 in a mixture of water and dispersant. The components can
be combined in a preground state. Another possibility, however, is
to comminute the constituents after they have been mixed, using a
rotor/stator disperser, a colloid mill or a bead mill.
[0127] The suspension prepared in this way is conveyed by the pump
2 via the heat exchanger 3 into the downstream jet disperser 4. In
addition to conveying, the pump also has the function of building
up the necessary dispersing pressure. Before entering the jet
disperser 4 the dispersion in the heat exchanger 3 is rapidly
heated to a temperature above the melting point of the solid phase,
so briefly forming an emulsion. This emulsion is then finely
homogenised in the jet disperser 4 and immediately after its
passage through the jet disperser is cooled in the cooling circuit
system 5/6. To minimize the cooling time, the dispersion is passed
into the condenser and recirculated using the pump 6 with
approximately a tenfold pumped circulation flow. As a result of the
cooling loop, quenching ensures that the emulsion is cooled within
a period of milliseconds and that the particles of active substance
solidify amorphously.
[0128] Following passage through the cooling circuit, the metering
pump 7 adds an aqueous solution of polyvinyl alcohol and also,
where appropriate, further coating materials and/or other additives
to the dispersion of amorphous particles. In one particular variant
of the process, however, it is also possible for the polyvinyl
alcohol solution used to encapsulate the amorphous particles to be
added as early as in the cooling circuit 5/6 or even in the
batching vessel 1.
[0129] Immediately thereafter the solution prestabilized in this
way is introduced into the spray dryer 8; here, the water is
removed from the dispersion, and the particles of active substance
are encapsulated by coating material.
[0130] The product in each case is a free-flowing powder. The
average size of the particles in the powder depends on the spray
drying conditions. Thus, with higher pressure and a greater amount
of air, the particles which form are smaller than when using lower
pressures and a smaller amount of air.
[0131] The formulations of the invention are redispersible powders
composed of finely divided active substance particles encapsulated
with coating material, the capsules in turn being embedded in
coating material.
[0132] The powder formulations of the invention are stable even
when stored for a relatively long period of time: They can be
converted to homogeneous spray liquids by stirring them into water.
These spray liquids are used by common methods, i.e., for example,
by spraying, pouring or injection. A further option is to granulate
the powders or to process them to tablets, pastes or other
application forms.
[0133] The application rate of the powder formulations of the
invention can be varied within a relatively wide range. The rate is
guided by the active substances present in each case and by the
amount thereof in the formulations.
[0134] By means of the powder formulations of the invention it is
possible to deliver active substances in a particularly
advantageous way. The active substances contained are readily
bioavailable and develop a biological activity which is
substantially better than that of those conventional formulations
in which the active components are present in the crystalline
state.
[0135] The Invention is Illustrated by the Following Examples.
PREPARATION EXAMPLES
Example 1
[0136] In a vessel, 3 litres of a suspension consisting of [0137] 5
parts by weight of the fungicidal active substance of the formula
##STR5## [0138] 5 parts by weight of emulsifier (phosphoric acid
mono-/diester mixture of a tristyrylphenol ethoxylate containing on
average 16 ethylene oxide units, tradename Soprophor.RTM. 3D33)
[0139] 0. 1 part by weight of silicone oil defoamer and [0140] 89.9
parts by weight of water were mixed and, using a bead mill, were
ground so that the particle size lies between 1 and 10 .mu.n. The
suspension thus prepared was pumped into a heat exchanger, heated
to 108.degree. C. and conveyed with a volume flow of 22 litres per
hour under a homogenizing pressure of 80 bar into a jet disperser
having a nozzle bore of 0.2 mm in diameter. The resultant
dispersion, in which the particles have an average size of 0.2
.mu.m, was cooled to a temperature of 30.degree. C. within
fractions of seconds, via a cooling circuit, then mixed with 1.2
litres of a 25% strength by weight solution of polyvinyl alcohol
(Mowiol.RTM. 3-83 from Clariant) in water and immediately
thereafter dried by means of a spray dryer with an air exit
temperature of <80.degree. C. This gave 550 g of a free-flowing
powder having an active substance content of 24.8%, the active
substance being in the amorphous state.
Example 2
[0141] In accordance with the method indicated in example 1 a
suspension of the composition set out therein was subjected to jet
dispersing under the conditions mentioned therein and, after
cooling to 30.degree. C., was mixed with 1.543 litres of a 25%
strength by weight solution of polyvinyl alcohol (Mowiol.RTM. 3-83
from Clariant) in water and with 600 g of primary fatty alcohol
ethoxylate (trade name: Dobanol 91-6 from Deutsche Shell Chemie
GmbH). Spray drying immediately thereafter gave 1 100 g of a
free-flowing powder having an active substance content of 11.86%,
the active substance being in the amorphous state.
Example 3
[0142] In a vessel, 3 litres of a suspension consisting of [0143] 5
parts by weight of the fungicidal active substance tebuconazole,
[0144] 5 parts by weight of the emulsifier specified in example 1,
[0145] 0.1 part by weight of silicone oil defoamer and [0146] 89.9
parts by weight of water were mixed and, using a bead mill, were
ground so that the particle size lies between 1 and 10 .mu.m. The
suspension thus prepared was pumped into a heat exchanger, heated
to 110.degree. C. and conveyed with a volume flow of 22 litres per
hour under a homogenizing pressure of 80 bar into a jet disperser
having a nozzle bore of 0.2 mm in diameter. The resultant
dispersion, in which the particles have an average size of 0.2
.mu.m, was cooled to a temperature of 30.degree. C. within
fractions of seconds by means of a cooling circuit, then mixed with
1.2 litres of a 25% strength by weight solution of polyvinyl
alcohol (Mowiol.RTM. 3-83 from Clariant) in water and immediately
thereafter was dried using a spray dryer with an air exit
temperature of <80.degree. C. This gave 550 g of a free-flowing
powder having an active substance content of 24.8%, the active
substance being in the amorphous state.
Example 4
[0147] In a vessel, 3 litres of a suspension consisting of [0148]
2.5 parts by weight of the fungicidal active substance
tebuconazole, [0149] 2.5 parts by weight of the fungicidal active
substance of the formula ##STR6## [0150] 5 parts by weight of the
emulsifier specified in example 1, [0151] 0.1 part by weight of
silicone oil defoamer and [0152] 89.9 parts by weight of water were
mixed and, using a bead mill, were ground so that the particle size
lies between 1 and 10 .mu.m. The suspension thus prepared was
pumped into a heat exchanger, heated to 110.degree. C. and conveyed
with a volume flow of 22 litres per hour under a homogenizing
pressure of 80 bar into a jet disperser having a nozzle bore of 0.2
mm in diameter. The resultant dispersion, in which the particles
have an average size of 0.2 .mu.m, was cooled to a temperature of
30.degree. C. within fractions of seconds by means of a cooling
circuit, then mixed with 1.2 litres of a 25% strength by weight
solution of polyvinyl alcohol (Mowiol.RTM. 3-83 from Clariant) in
water and immediately thereafter was dried using a spray dryer with
an air exit temperature of <80.degree. C. This gave 550 g of a
free-flowing powder having an active substance content of 24.5%,
the active substance being in the amorphous state.
Comparative Example I
[0153] In a vessel, 3 litres of a suspension consisting of [0154] 5
parts by weight of the fungicidal active substance of the formula
##STR7## [0155] 5 parts by weight of the emulsifier specified in
example 1, [0156] 0.1 part by weight of silicone oil defoamer and
[0157] 89.9 parts by weight of water were mixed and, using a bead
mill, were ground so that the particle size lies between 1 and 10
.mu.m. The suspension thus prepared was pumped into a heat
exchanger, heated to 108.degree. C. and conveyed with a volume flow
of 22 litres per hour under a homogenizing pressure of 80 bar into
a jet disperser having a nozzle bore of 0.2 mm in diameter. The
resultant dispersion, in which the particles have an average size
of 0.2 .mu.m (measured by the photon correlations spectroscopy=PSC
method), was cooled to a temperature of 30.degree. C. within
fractions of seconds, via a cooling circuit, then dried by means of
a spray dryer with a gas exit temperature of 80.degree. C. It was
not possible to produce a free-flowing powder. The dried material
sticks in the dryer and has a crystalline structure.
Comparative Example II
[0158] In a vessel, 3 litres of a suspension consisting of [0159] 5
parts by weight of the fungicidal active substance of the formula
##STR8## [0160] 5 parts by weight of the emulsifier specified in
example 1, [0161] 0.1 part by weight of silicone oil defoamer and
[0162] 89.9 parts by weight of water were mixed and, using a bead
mill, were ground so that the particle size lies between 1 and 10
.mu.m. The suspension thus prepared was pumped into a heat
exchanger, heated to 108.degree. C. and conveyed with a volume flow
of 22 litres per hour under a homogenizing pressure of 80 bar into
a jet disperser having a nozzle bore of 0.2 mm in diameter. The
resultant dispersion, in which the particles have an average size
of 0.2 .mu.m (measured by the photon correlations spectroscopy=PSC
method), was cooled to a temperature of 30.degree. C. within
fractions of seconds, via a cooling circuit, and then mixed with an
amount of 25% strength by weight solution of polyvinyl alcohol
(Mowiol.RTM. 3-83 from Clariant) in water such that the polyvinyl
alcohol fraction in the resultant product was 15% by weight.
Subsequent spray drying at an air exit temperature of
<80.degree. C. gave 300 g of a powder with a slight degree of
agglomeration and with an active substance content of 40%. The
crystalline fraction of active substance was 1% and rose during
storage of the product.
Use Example A
[0163] Penetration Test
[0164] This test measured the penetration of active substance
through enzymatically isolated cuticles of apple tree leaves.
[0165] The leaves used were cut in free developed state from apple
trees of the Golden Delicious variety. The cuticles were isolated
as follows: [0166] first of all, leaf discs labelled on the
underside with dye and formed by punching were filled by means of
vacuum infiltration with a solution (0.2 to 2% strength) buffered
to a pH of between 3 and 4, [0167] then sodium azide was added and
[0168] the leaf discs thus treated were left to stand until the
original leaf structure broke down and the non-cellular cuticles
underwent detachment.
[0169] Subsequently, only those cuticles from the top leaf sides
which were free from stomata and hairs were used. They were washed
a number of times in alternation with water and with a buffer
solution with a pH of 7. The clean cuticles obtained were, finally,
applied to Teflon platelets, smoothed with a gentle air jet and
dried.
[0170] In the next step, the cuticle membranes obtained in this way
were placed in diffusion cells (i.e. transit chambers) made of
stainless steel for membrane transport investigations. For these
investigations the cuticles were placed centrally using tweezers on
the edges of the diffusion cells, which were coated with silicone
grease, and were sealed with a ring, which was likewise greased.
The arrangement had been chosen so that the morphological outer
face of the cuticles was pointing outwards, i.e. to the air, while
the original inner face was facing the inside of the diffusion
cell. The diffusion cells were filled with water or a mixture of
water and solvent.
[0171] To determine the penetration, 9 .mu.l of a spray liquor of
the composition indicated below were applied to the outer face of
each cuticle.
[0172] Spray Liquor A (Inventive)
[0173] Powder formulation from example 2 in 1 litre of water.
[0174] Active Substance Content 1 000 ppm
[0175] Spray Liquor B (Known)
[0176] Conventional water-dispersible powder of the fungicidal
active substance indicated in example 1 in 1 litre of water.
[0177] Active substance content 1 000 ppm
[0178] CIPAC-C water was used in the spray liquors in each
case.
[0179] After the spray liquors had been applied the water was
evaporated in each case, then each of the chambers was turned round
and placed in thermostated troughs, containing in each case a
saturated aqueous calcium nitrate tetrahydrate solution below the
outer face of the cuticles. The penetration which occurred
therefore took place at a relative atmospheric humidity of 56% and
a set temperature of 25.degree. C. At regular intervals, samples
were taken with a syringe and analyzed by HPLC for the amount of
penetrated active substance.
[0180] The results of the experiments are evident from the
following table. The numbers reported are average values of 8
measurements. TABLE-US-00001 TABLE A Active substance penetration
in % after 24 h 48 h 72 h A 6.4 7.1 7.7 B 0.6 0.9 1.2
Use Example B
[0181] Erysiphe Test (Wheat)/Curative
[0182] Dispersant: 1 part by weight of the emulsifier specified in
example 1
[0183] A power formulation according to example 1 is diluted to the
desired concentration with water, with addition of dispersant.
[0184] To test for curative activity, young plants are dusted with
spores of Erysiphe graminis f.sp. tritici. 48 hours after
inoculation, the plants are sprayed with the active substance
formulation at the application rate indicated.
[0185] The plants are placed in a glasshouse at a temperature of
approximately 18.degree. C. and a relative atmospheric humidity of
approximately 80% in order to promote the development of mildew
pustules.
[0186] Evaluation takes place 9 days after inoculation. 0% denotes
an efficacy which conforms to that of the control, whereas an
efficacy of 100% means that no infestation is observed.
[0187] Application rates and experimental results are evident from
the following table. TABLE-US-00002 TABLE B Erysiphe Test
(wheat)/curative Active substance Application rate of formulation
from Example active substance in g/ha Efficacy in % Inventive: 1 25
86
* * * * *